Derivatives of [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)alkyl]phosphonic Acid and Methods of Making Them

ABSTRACT

Compounds of formula (I) or pharmaceutically acceptable salts thereof are provided:  
                 
wherein: A is alkylenyl of 1 to 4 carbon atoms, or alkenylenyl of 2 to 4 carbon atoms; 
         R 1  and R 2  are, independently, hydrogen or a C 5  to C 7  aryl optionally substituted with 1 to 2 substituents, independently, selected from the group consisting of —C(O)R 3 , halogen, cyano, nitro, hydroxyl, C 1 -C 6  alkyl, and C 1 -C 6  alkoxy,    with the proviso that at least one of R 1  and R 2  is not hydrogen;    R 3  is, independently, hydrogen, —OR 4 , alkyl, aryl, or heteroaryl;    R 4  is hydrogen, alkyl, aryl, or heteroaryl;    R 5  and R 6  are, independently, hydrogen, alkyl, hydroxyl, alkoxy, or C 5  to C 7  aryl;    wherein any R 3  to R 6  group having an aryl or heteroaryl moiety can optionally be substituted on the aryl or heteroaryl moiety with 1 to about 5 substituents, independently, selected from the group consisting of halogen, cyano, nitro, hydroxyl, C 1 -C 6  alkyl, and C 1 -C 6  alkoxy. Methods of making these compounds as well as methods using the compounds for treating a variety of conditions are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Application No. 60/617,023,filed Oct. 8, 2004, the entire disclosure of which is incorporatedherein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to derivatives of[2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)alkyl]phosphonicacid and methods of making them. The compounds of the present inventionare particularly useful as N-methyl-D-aspartate (NMDA) receptorantagonists.

Glutamate and aspartate play dual roles in the central nervous system asessential amino acids and as the principal excitatory neurotransmitters.There are at least four classes of excitatory amino acid receptors:NMDA, AMPA (2-amino-3-(methyl-3-hydroxyisoxazol-4-yl)propanoic acid),kainate, and metabotropic receptors. These excitatory amino acidreceptors regulate a wide range of signaling events that impactphysiological brain functions. For example, activation of the NMDAreceptor has been shown to be the central event that leads toexcitotoxicity and neuronal death in many disease states, as well as aresult of hypoxia and ischaemia following head trauma, stroke, andfollowing cardiac arrest. It is also known that the NMDA receptor playsa major role in the synaptic plasticity that underlies many highercognitive functions, such as memory and learning, certain nociceptivepathways, and in the perception of pain. In addition, certain propertiesof NMDA receptors suggest that they may be involved in theinformation-processing in the brain that underlies consciousness itself.

NMDA receptors are localized throughout the central nervous system. NMDAreceptors are ligand-gated cation channels that modulate sodium,potassium, and calcium ions flux when they are activated by glutamate incombination with glycine. Structurally, the NMDA receptor is thought tobe comprised of heteromultimeric channels containing two major subunitsdesignated as NR1 and NR2. These subunits contain a glycine bindingsite, a glutamate binding site, and a polyamine binding site. For theNR1 subunit, multiple splice variants have been identified, whereas forthe NR2 subunit, four individual subunit types (NR2A, NR2B, NR2C, andNR2D) have been identified. The NMDA receptor also contains an Mg⁺⁺binding site located inside the pore of the ionophore of the NMDAreceptor/channel complex, which blocks the flow of ions.

Substantial preclinical and clinical evidence indicates that inhibitorsof the NMDA receptor have therapeutic potential for treating numerousdisorders. Disorders believed to be responsive to inhibition of NMDAreceptors include cerebral vascular disorders, such as cerebral ischemia(e.g., stroke) or cerebral infarction resulting in a range ofconditions, such as thromboembolic or hemorrhagic stroke, or cerebralvasospasm; cerebral trauma; muscular spasm; and convulsive disorders,such as epilepsy or status epilepticus. NMDA receptor antagonists mayalso be used to prevent tolerance to opiate analgesia or to help controlsymptoms of withdrawal from addictive drugs.

Screening of compounds in recent years have identified a number of NMDAreceptor antagonists that have been used in animal and clinical humanstudies to demonstrate proof of concept for the treatment of a varietyof disorders. The difficulty with demonstrating clinical utility of NMDAreceptor antagonists has generally been the antagonists' lack of NMDAreceptor subtype selectivity and/or biological activity, when dosedorally. Thus, the search for NMDA receptor antagonists that aresubtype-selective and/or orally efficacious continues.

SUMMARY OF THE INVENTION

In one embodiment, the invention provides compounds of formula (I) or apharmaceutically acceptable salt thereof:

wherein:

A is alkylenyl of 1 to 4 carbon atoms or alkenylenyl of 2 to 4 carbonatoms;

R₁ and R₂ are, independently, hydrogen or a C₅ to C₇ aryl optionallysubstituted with 1 to 2 substituents, independently, selected from thegroup consisting of —C(O)R₃, halogen, cyano, nitro, hydroxyl, C₁-C₆alkyl, and C₁-C₆ alkoxy;

with the proviso that at least one of R₁ and R₂ is not hydrogen;

R₃ is hydrogen, —OR₄, alkyl, aryl, or heteroaryl, and

R₄ is hydrogen, alkyl, aryl, or heteroaryl,

R₅ and R₆ are, independently, hydrogen, alkyl, OH, alkoxy, or C₅ to C₇aryl;

wherein any R₃ to R₆ group having an aryl or heteroaryl moiety mayoptionally be substituted on the aryl or heteroaryl moiety with 1 toabout 5 substituents, independently, selected from the group consistingof halogen, cyano, nitro, hydroxyl, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

In some further embodiments, the invention provides compounds of formula(II) or pharmaceutically acceptable salt thereof:

wherein:

R₁ and R₂ are, independently, hydrogen or

with the proviso that at least one of R₁ and R₂ is not hydrogen;

R₃ is hydrogen, —OR₄, alkyl, aryl, or heteroaryl,

R₄ is hydrogen, alkyl, aryl, or heteroaryl,

R₅ and R₆ are, independently, hydrogen, alkyl, OH, alkoxy, or C₅ to C₇aryl;

wherein any R₃ to R₆ group having an aryl or heteroaryl moiety mayoptionally be substituted on the aryl or heteroaryl moiety with 1 toabout 5 substituents, independently, selected from the group consistingof halogen, cyano, nitro, hydroxyl, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

In some further embodiments, the invention includes compounds of formula(III) or pharmaceutically acceptable salt thereof:

wherein:

R₁ and R₂ are, independently, hydrogen or

with the proviso that at least one of R₁ and R₂ is not hydrogen;

R₃ is hydrogen, alkyl, aryl, or heteroaryl, and

wherein any aryl or heteroaryl moiety may optionally be substituted onthe aryl or heteroaryl moiety with 1 to about 5 substituents,independently, selected from the group consisting of halogen, cyano,nitro, hydroxyl, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

In other embodiments, the invention provides a compound of formula (III)or pharmaceutically acceptable salt thereof:

wherein:

R₁ and R₂ are, independently, hydrogen or

with the proviso that at least one of R₁ and R₂ is not hydrogen;

R₃ is —OR₄,

R₄ is hydrogen, alkyl, aryl, or heteroaryl; and

wherein any aryl or heteroaryl moiety may optionally be substituted onthe aryl or heteroaryl moiety with 1 to about 5 substituents,independently, halogen, cyano, nitro, hydroxyl, C₁-C₆ alkyl, or C₁-C₆alkoxy.

In still other embodiments, the invention provides a compositioncomprising at least one compound of formula (I), (II), (III), andpharmaceutically acceptable salts thereof, described above.

In some further embodiments, the invention provides methods of makingthe compounds of formula (I), (II), (III), and pharmaceuticallyacceptable salts thereof, wherein the method comprises the steps of:

reacting a compound of formula (2)

or a pharmaceutically acceptable salt thereof, with a compound offormula (3)

wherein A₁ is alkenyl having 2 to 4 carbon atoms or alkynyl having 2-4carbon atoms, under conditions effective to form a compound of formula(I), or a pharmaceutically acceptable salt thereof.

In some further embodiments, the invention provides methods for making acompound of formula (I), (II), (III), and pharmaceutically acceptablesalts thereof, comprising the steps of:

treating a disubstituted diaminoalkane derivative of formula (6)

wherein Pg is a protecting group, with a dialkoxysquarate of formula (1)

wherein R is alkoxy, preferably C₁-C₄ alkoxy, in a suitable solvent toyield a tri-substituted diaminoalkane derivative of formula (7)

deprotecting and cyclizing the tri-substituted diaminoalkane derivativeof formula (7) to produce a compound of formula (I).

In other embodiments, the invention provides a product made by any ofthe foregoing processes.

In other embodiments, the invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound of formula (I), (II), (III), and pharmaceuticallyacceptable salts thereof, described above.

In further embodiments, the invention provides methods for treating atleast one condition in a mammal selected from the group consisting ofcerebral vascular disorder selected from the group consisting ofcerebral ischemia, cerebral infarction, cerebral vasospasm, andcombinations thereof; cerebral trauma; muscular spasm; a convulsivedisorder selected from the group consisting of epilepsy, statusepilepticus, and combinations thereof; hypoglycemia; cardiac arrest;asphyxia anoxia; spinal chord injury, and combinations thereof,comprising the step of:

administering to said mammal in need thereof an effective amount of atleast one compound of formula (I), (II), (III), and pharmaceuticallyacceptable salts thereof, described above.

In further embodiments, the invention provides methods for treating atleast one condition in a mammal selected from the group consisting ofglaucoma, diabetic end organ complications, and combinations thereof,comprising the step of:

administering to a mammal in need thereof an effective amount of atleast one compound of formula (I), (II), (III), and pharmaceuticallyacceptable salts thereof, described above.

In further embodiments, the invention provides methods for treating atleast one condition in a mammal selected from the group consisting ofanxiety disorder; mood disorder; schizophrenia; schizophreniformdisorder; schizoaffective disorder, and combinations thereof, comprisingthe step of:

administering to a mammal in need thereof an effective amount of atleast one compound of formula (I), (II), (III), and pharmaceuticallyacceptable salts thereof, described above.

In further embodiments, the invention provides methods for treating atleast one neurodegenerative disorder in a mammal selected from the groupconsisting of Parkinson's disease, Huntingdon's disease, Alzheimer'sdisease, amyotrophic lateral sclerosis, chronic dementia, cognitiveimpairment, and combinations thereof, comprising the step of:

administering to a mammal in need thereof an effective amount of atleast one compound of formula (I), (II), (III), and pharmaceuticallyacceptable salts thereof, described above.

In further embodiments, the invention provides methods for treating atleast one condition in a mammal selected from the group consisting ofinflammatory diseases; fibromyalgia; complications from herpes zoster;prevention of tolerance to opiate analgesia; withdrawal symptoms fromaddictive drugs, and combinations thereof, comprising the step of:

administering to a mammal in need thereof an effective amount of atleast one compound of formula (I), (II), (III), and pharmaceuticallyacceptable salts thereof, described above.

In further embodiments, the invention provides methods for treating painin a mammal, comprising the step of:

administering to a mammal in need thereof an effective amount of atleast one compound of formula (I), (II), (III), and pharmaceuticallyacceptable salts thereof, described above.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides compounds of formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein:

A is alkylenyl of 1 to 4 carbon atoms or alkenylenyl of 2 to 4 carbonatoms;

R₁ and R₂ are, independently, hydrogen, or a C₅ to C₇ aryl optionallysubstituted with 1 to 2 substituents, independently, selected from thegroup consisting of —C(O)R₃, halogen, cyano, nitro, hydroxyl, C₁-C₆alkyl, and C₁-C₆ alkoxy;

with the proviso that at least one of R₁ and R₂ is not hydrogen;

R₃ is hydrogen, —OR₄, alkyl, aryl, or heteroaryl, and

R₄ is hydrogen, alkyl, aryl, or heteroaryl,

R₅ and R₆ are, independently, hydrogen, alkyl, hydroxyl, alkoxy, or C₅to C₇ aryl;

wherein any R₃ to R₆ group having an aryl or heteroaryl moiety mayoptionally be substituted on the aryl or heteroaryl moiety with 1 toabout 5 substituents, independently, selected from the group consistingof halogen, cyano, nitro, hydroxyl, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

In some further embodiments, the invention provides a compound offormula (II) or pharmaceutically acceptable salt thereof:

wherein:

R₁ and R₂ are, independently, hydrogen or

with the proviso that at least one of R₁ and R₂ is not hydrogen;

R₃ is hydrogen, —OR₄, alkyl, aryl, or heteroaryl,

R₄ is hydrogen, alkyl, aryl, or heteroaryl,

R₅ and R₆ are, independently, hydrogen, alkyl, OH, alkoxy, or C₅ to C₇aryl;

wherein any R₃ to R₆ group having an aryl or heteroaryl moiety mayoptionally be substituted on the aryl or heteroaryl moiety with 1 toabout 5 substituents, independently, selected from the group consistingof halogen, cyano, nitro, hydroxyl, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

In some embodiments, the compounds of formula (II) are preferredcompounds of formula (I).

In some further embodiments, the invention includes a compound offormula (III) or pharmaceutically acceptable salt thereof:

wherein:

R₁ and R₂ are, independently, hydrogen or

with the proviso that at least one of R₁ and R₂ is not hydrogen;

R₃ is hydrogen, alkyl, aryl, or heteroaryl; and

wherein any aryl or heteroaryl moiety may optionally be substituted onthe aryl or heteroaryl moiety with 1 to about 5 substituents,independently, selected from the group consisting of halogen, cyano,nitro, hydroxyl, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

In certain embodiments, the compounds of formula (III) are preferredcompounds of formula (II) and, in turn, preferred compounds of formula(I).

In other embodiments, the invention provides a compound of formula (III)or pharmaceutically acceptable salt thereof:

wherein:

R₁ and R₂ are, independently, hydrogen or

with the proviso that at least one of R₁ and R₂ is not hydrogen;

R₃ is —OR₄;

R₄ is hydrogen, alkyl, aryl, or heteroaryl; and

wherein any aryl or heteroaryl moiety may optionally be substituted onthe aryl or heteroaryl moiety with 1 to about 5 substituents,independently, halogen, cyano, nitro, hydroxyl, C₁-C₆ alkyl, or C₁-C₆alkoxy.

In certain embodiments, the compounds of formula (III) are preferredcompounds of formula (II) and, in turn, preferred compounds of formula(I).

In some embodiments, the compounds of formula (II) are preferredcompounds of formula (I).

In certain embodiments, the compounds of formula (III) are preferredcompounds of formula (II) and, in turn, preferred compounds of formula(I).

Unless otherwise indicated:

“Alkyl,” as used herein, refers to an aliphatic hydrocarbon chain having1 to 12 carbon atoms and includes, but is not limited to, straight orbranched chains, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl,and isohexyl. Lower alkyl refers to alkyl having 1 to 3 carbon atoms. Insome embodiments of the invention, alkyl is preferably C₁ to C₈ and,more preferably, C₁ to C₆.

“Alkylenyl,” as used herein, refers to a linking alkyl group (orbivalent alkyl group), e.g., —CH₂. or —(CH₂)₂—.

“Alkenyl,” as used herein, refers to an aliphatic straight or branchedhydrocarbon chain having 2 to 7 carbon atoms that contains 1 to 3 doublebonds. Examples of alkenyl are straight or branched mono-, di-, orpolyunsaturated groups, such as vinyl, prop-1-enyl, allyl, methallyl,but-1-enyl, but-2-enyl or but-3-enyl.

“Alkenylenyl,” as used herein, refers to a linking alkenyl group (or abivalent alkenyl group)

“Alkynyl,” as used herein, refers to an aliphatic, straight or branched,hydrocarbon chain having 2 to 7 carbon atoms that may contain 1 to 3triple bonds.

“Acyl,” as used herein, refers to the group R—C(═O)— where R is an alkylgroup of 1 to 6 carbon atoms. For example, a C₂ to C₇ acyl group refersto the group R—C(═O)— where R is an alkyl group of 1 to 6 carbon atoms.

“Alkanesulfonyl,” as used herein, refers to the group R—S(O)₂— where Ris an alkyl group of 1 to 6 carbon atoms.

“Aryl,” as used herein, refers to an aromatic 5- to 13-membered mono- orbi-carbocyclic ring, such as phenyl or naphthyl. Preferably, groupscontaining aryl moieties are monocyclic having 5 to 7 carbon atoms inthe ring. Heteroaryl means an aromatic 5- to 13-membered, carboncontaining, mono- or bi-cyclic ring having one to five heteroatoms that,independently, may be selected from nitrogen, oxygen and sulfur.Preferably, groups containing heteroaryl moieties are monocyclic having5 to 7 members in the ring where one to two of the ring members areselected, independently, from nitrogen, oxygen or sulfur. Groupscontaining aryl or heteroaryl moieties may optionally be substituted asdefined below or unsubstituted.

“Aroyl,” as used herein, refers to the group Ar—C(═O)— where Ar is arylas defined above. For example, a C₆ to C₁₄ aroyl moiety refers to thegroup Ar—C(═O)— where Ar is an aromatic 5 to 13 membered carbocylicring.

“Halogen,” as used herein, means fluorine, chlorine, bromine or iodine.

“Substituted,” as used herein, refers to a moiety, such as an aryl orheteroaryl, moiety having from 1 to about 5 substituents, and morepreferably from 1 to about 3 substituents, independently, selected fromthe group consisting of halogen, cyano, nitro, hydroxyl, C₁-C₆ alkyl,and C₁-C₆ alkoxy. Preferred substituents are halogen, hydroxyl, or C₁-C₆alkyl.

In some embodiments of the present invention, R₅ and R₆ are preferably,independently or the same, hydrogen, C₁-C₆ alkyl, or hydroxyl, and morepreferably hydrogen.

In other embodiments, A is preferably an alkylenyl group, —(CH₂)_(n)—,where n is 1 to 3, more preferably 1 to 2 and most preferably 2.

In other embodiments, R₁ and R₂ are, independently, hydrogen or

In some embodiments, R₁ and R₂ are the same. In another embodiment, bothR₁ and R₂ are not hydrogen.

In other embodiments,R₃ is independently hydrogen, —OR₄, alkyl, aryl, orheteroaryl. In yet other embodiments, R₃ is hydrogen, —OR₄, or C₁ to C₆alkyl.

In other embodiments, R₄ is hydrogen, alkyl, aryl, or heteroaryl. In yetother embodiments, R₄ is hydrogen or C₁ to C₆ alkyl, e.g., ethyl.

In other embodiments, R₁ and R₂ are preferably, independently, hydrogenor

with the proviso that at least one of R₁ and R₂ is not hydrogen;

R₃ is independently hydrogen, —OR₄, alkyl, aryl, or heteroaryl, and

R₄ is hydrogen, alkyl, aryl, or heteroaryl.

In yet other embodiments, R₁ and R₂ are preferably, independently,hydrogen or

with the proviso that at least one of R₁ and R₂ is not hydrogen;

R₃ is hydrogen, —OR₄, or C₁ to C₆ alkyl; and

R₄ is hydrogen or C₁ to C₆ alkyl.

In further preferred embodiments of the invention,

A is an alkylenyl group having the formula —(CH₂)_(n)—;

n is 2;

R₁ and R₂ are H or

with the proviso that at least one of R₁ and R₂ is not hydrogen;

R₃ is a C₁ to C₃ alkyl, preferably methyl, or —OR₄;

R₄ is a C₁ to C₃ alkyl, preferably, ethyl.

In certain preferred embodiments, R₅ and R₆ are both hydrogen.

In some preferred embodiments, the carbonyl substituent on the phenylring can be at the 2-, 3-, or 4-position of the phenyl ring and, morepreferably, at the 3-position of the phenyl ring (such as the firstpreferred compound below).

Some preferred examples of compounds of the present invention includethe following:

diethyl3,3′-[({2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphoryl)bis(oxy)]dibenzoate(Example 1);

diethyl2,2′-[({2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphoryl)bis(oxy)]dibenzoate;

diethyl4,4′-[({2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphoryl)bis(oxy)]dibenzoate;

bis(4-acetylphenyl){2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphonate;

bis(3-acetylphenyl){2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphonate;

bis(2-acetylphenyl){2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphonate;

or a pharmaceutically acceptable salt thereof.

In further embodiments, the invention provides compounds of formula (I),(II), (III), and pharmaceutically acceptable salts thereof, where one ofR₁ and R₂ is hydrogen.

The compounds of this invention may contain asymmetric carbon atomsand/or phosphorus atoms, and thus can give rise to optical isomers anddiastereoisomers. While shown without respect to stereochemistry informula (I), (II) or (III), or a pharmaceutically acceptable saltthereof, the present invention includes such optical isomers anddiastereoisomers; as well as the racemic and resolved, enantiomericallypure R and S stereoisomers; as well as other mixtures of the R and Sstereoisomers and pharmaceutically acceptable salts thereof.

Where an enantiomer is preferred, it may, in some embodiments beprovided substantially free of the corresponding enantiomer. Thus, anenantiomer substantially free of the corresponding enantiomer refers toa compound which is isolated or separated via separation techniques orprepared free of the corresponding enantiomer. “Substantially free,” asused herein, means that the compound is made up of a significantlygreater proportion of one enantiomer. In preferred embodiments, thecompound is made up of at least about 90% by weight of a preferredenantiomer. In other embodiments of the invention, the compound is madeup of at least about 99% by weight of a preferred enantiomer. Preferredenantiomers may be isolated from racemic mixtures by any method known tothose skilled in the art, including high performance liquidchromatography (HPLC) and the formation and crystallization of chiralsalts or prepared by methods described herein. See, for example,Jacques, et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725(1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill,NY, 1962); Wilen, S. H. Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972).

One skilled in the art will also recognize that it is possible fortautomers to exist of formula (I), (II), (III), and pharmaceuticallyacceptable salts thereof. The present invention includes all suchtautomers even though not shown in formula (I), (II), (III), andpharmaceutically acceptable salts thereof.

The compounds useful in the present invention also includepharmaceutically acceptable salts of the compounds of formula (I), (II),or (III). By “pharmaceutically acceptable salt”, it is meant anycompound formed by the addition of a pharmaceutically acceptable baseand a compound of formula (I), (II), or (III) to form the correspondingsalt. By the term “pharmaceutically acceptable” it is meant a substancethat is acceptable for use in pharmaceutical applications from atoxicological perspective and does not adversely interact with theactive ingredient. Preferably, the pharmaceutically acceptable salts arealkali metal (sodium, potassium, lithium) or alkaline earth metal(calcium, magnesium) salts of the compounds of formula (I), (II), or(III), or salts of the compounds of formula (I), (II), or (III) withpharmaceutically acceptable cations derived from ammonia or a basicamine. Examples of the later include, but are not limited to, ammonium,mono-, di-, or trimethylammonium, mono-, di-, or triethylammonium,mono-, di-, or tripropylammonium (iso and normal),ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium,benzylammonium, dibenzylammonium, piperidinium, morpholinium,pyrrolidinium, piperazinium, 1-methylpiperidinium, 1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium,1-n-butylpiperidinium, 2-methylpiperidinium,1-ethyl-2-methylpiperidinium, mono-, di-, or triethanolammonium,tris-(hydroxymethyl)methylammonium, or phenylmono ethanolammonium.

The compounds of the present invention, including compounds of formula(I), (II), (III), and pharmaceutically acceptable salts thereof, can beprepared according to the following schemes and methods:

The compounds of general formula (I) can be conveniently prepared asshown in Scheme 1. Thus, reaction of a diaminoalkane with andialkoxysquarate (1) in a suitable protic solvent, such as methanol,ethanol and the like, at a temperature ranging from about 0° C. to about50° C., preferably at a temperature ranging from about 20° C. to about30° C., provides the bicyclic intermediate of formula (2). By “suitablesolvent” it is meant a solvent in which both the amine and the squarateare at least partially soluble and with which both are substantiallynon-reactive. Typically, the reaction time is about 10 hours to about 25hours, and more preferably about 12 hours to about 18 hours.

In some preferred embodiments, the diaminopropane is 1,3-diaminopropane.In some preferred embodiments, R is C₁ to C₄ alkoxy. Most preferably,the dialkoxysquarate is diethoxysquarate, where each R is —OEt. In someembodiments, R₅ and R₆ are both hydrogen. In further embodiments, R₅ andR₆ are, independently, hydrogen, alkyl, hydroxyl, alkoxy, or C₅ to C₇aryl. Each of the alkyl, alkoxy, and C₅ to C₇ aryl may optionally besubstituted as discussed above.

The anion of the bicyclic intermediate (2) can be formed by contacting(2) with a suitable base, such as a hydride or alkoxide, including, forexample, sodium methoxide, potassium t-butoxide, sodium hydride or thelike, in a suitable aprotic solvent, such as N,N-dimethylformamide ortetrahydrofuran. The anion is then treated with the phosphonate esterintermediate (3), where preferably A₁ is (CH₂)₂, but may be C₂-C₄alkenyl or C₂-C₄ alkynyl, and preferably R₁ and R₂ are:

The mixture is stirred at ambient temperature from about 10 hours toabout 25 hours, more preferably from about 12 to about 18 hours. Thedesired compound of formula (I) is isolated from the reaction mixtureusing suitable purification techniques, such as flash chromatography orhigh-pressure liquid chromatography.

The phosphonate ester intermediate (3) can be prepared by alkylation ofa compound of formula (4) with a phosphono dihalide (i), where X is ahalide, A₁ is as defined above, and R₁ and R₂ are:

in a suitable aprotic solvent, such as dichloromethane or the like, attemperatures ranging from about 0° C. to about 30° C. In a preferredembodiment, A₁ is (CH₂)₂ and X is Cl. The reaction time is from about 10hours to about 25 hours, and more preferably from about 12 hours toabout 16 hours. By “suitable solvent” it is meant a solvent in whichboth reagents are at least partially soluble and with which bothreagents are substantially non-reactive. Preferably an acid scavenger(to react with the acid halide by-product of the reaction), such as anorganic amine is optionally added to the reaction mixture in thereaction to form intermediate (3). The organic amine is preferably asecondary or tertiary amine and more preferably a tertiary amine, suchas triethylamine.

Alternatively, the compounds of formula (I), (II), (III), andpharmaceutically acceptable salts thereof, can be obtained as shown inScheme 2 by adding the intermediate (3), one preparation of which isdescribed above, to a mono-protected diaminoalkane (5) at ambienttemperature and in a suitable aprotic solvent, such as tetrahydrofuran.The diaminoalkane may be mono-protected using a suitable protectinggroup Pg, such as t-butoxycarbonyl. The resulting disubstituteddiaminoalkane derivative (6) is treated preferably at ambienttemperature, with a dialkoxysquarate (1) in a suitable solvent, such asacetonitrile to provide the tri-substituted diaminoalkane derivative(7). The latter (7) is deprotected, for example, using trifluoroaceticacid in a suitable aprotic solvent, such as methylene chloride afterwhich cyclization is accomplished using, for example, an organic base,preferably a tertiary amine, such as triethylamine in a suitablesolvent, such as acetonitrile. Those of skill in the art will readilyrecognize suitable protecting groups which may be used in thissynthesis.

More specific syntheses of exemplary compounds of the invention aredetailed in the Examples below.

The compounds of the present invention, including compounds of formula(I), (II), (III), and pharmaceutically acceptable salts thereof, whenadministered to mammals, are NMDA antagonists, and are thus useful fortreating a variety of disorders that benefit from inhibiting the NMDAreceptor in mammals. By “treat” or “treating,” as used herein, it ismeant at least partially or completely alleviating, inhibiting,preventing, ameliorating and/or relieving the disorder. For example,“treat” and “treating,” as used herein, includes partially or completelyalleviating, ameliorating, or relieving the condition in question. Also,for example, “treat” and “treating” is meant to include totally orpartially inhibiting (i.e., preventing) the development of pain.

“Mammals,” as used herein, refers to warm blooded vertebrate animals,such as humans.

Accordingly, the present invention provides methods for treatingconditions in mammals that would benefit from inhibiting the NMDAreceptor that includes administering to a mammal in need thereof atherapeutically effective amount of at least one compound of formula(I), (II), (III), and pharmaceutically acceptable salts thereof.

While in no way intending to be bound in theory, it is believed that thecompounds of the present invention after administration into a mammal,form the corresponding phosphonic acid (i.e., where R₁ and/or R₂ arehydrogen in formula (I)). It has surprisingly been discovered thatcompounds of the present invention relative to such correspondingphosphonic acids have improved bioavailability when administered orallyto mammals. Additionally, the compounds of the present invention, afteradministration into mammals, have a unique affinity and selectivity forcertain binding sites on the NMDA receptor. This unique affinity andselectivity is believed to provide effective treatment at lower dosesand/or cause fewer side effects at doses to provide the desiredtreatment. This is particularly evident when the condition being treatedis pain.

In other embodiments, the present invention provides methods fortreating one or more conditions associated with a glutamate abnormalitythat includes administering orally to a mammal in need thereof atherapeutically effective amount of at least one compound of formula(I), (II), (III), and pharmaceutically acceptable salts thereof. As usedherein, “associated with” refers to conditions directly or indirectlycaused by a glutamate abnormality. “Glutamate abnormality” refers to anycondition produced by a disease or a disorder in which glutamate and/orits receptors are implicated as a contributing factor to the disease ordisorder. Conditions believed to be associated with a glutamateabnormality include, but are not limited to, vascular disordersassociated with a glutamate abnormality, such as cerebral vasculardisorders including, but not limited to, cerebral ischemia (e.g.,stroke) or cerebral infarction resulting in a range of conditions, suchas thromboembolic or hemorrhagic stroke, or cerebral vasospasm; cerebraltrauma; muscular spasm; convulsive disorders, such as epilepsy or statusepilepticus; glaucoma; pain; anxiety disorders, such as panic attack,agoraphobia, panic disorder, specific phobia, social phobia, obsessivecompulsive disorder, posttraumatic stress disorder, acute stressdisorder, generalized anxiety disorder, separation anxiety disorder, orsubstance-induced anxiety disorder; mood disorders, such as bipolardisorders (e.g., bipolar I disorder, bipolar II disorder, andcyclothymic disorder), depressive disorders (e.g., major depressivedisorder, dysthymic disorder, and substance-induced mood disorder), moodepisodes (e.g., major depressive episode, manic episode, mixed episode,and hypomanic episode); schizophrenia; schizophreniform disorder;schizoaffective disorder; cognitive impairment, such as memory loss; andchronic neurodegenerative disorders, such as Parkinson's disease,Huntington's disease, Alzheimer's disease, amyotrophic lateralsclerosis, or chronic dementia related to, for example, Lewy bodydisease, Alzheimer's disease, fronto temporal dementia, or AIDS. Withrespect to the mental disorders listed above, such as schizophrenia,mood disorders and anxiety disorders, reference is made to theDiagnostic and Statistical Manual of Mental Disorders, 4th edition,Washington, D.C., American Psychiatric Association (1994) for a morecomplete description of each of the mental disorder.

Additional conditions believed to be related to glutamate abnormalitiesinclude inflammatory diseases; hypoglycemia; diabetic end organcomplications; cardiac arrest; asphyxia anoxia, such as from neardrowning, pulmonary surgery and cerebral trauma; and spinal cord injury.The compounds of the present invention may also be used to treatfibromyalgia, irritable bowel syndrome, and complications from herpeszoster (shingles), such as prevention of post-herpetic neuralgia. Thecompounds in the present invention may also be used to prevent toleranceto opiate analgesia or to help control symptoms of withdrawal fromaddictive drugs. Thus, the present invention provides methods fortreating each of the aforementioned conditions that includesadministering orally to a mammal in need thereof a therapeuticallyeffective amount of at least one compound of formula (I), (II), or(III).

In one preferred embodiment, the compounds useful in the presentinvention are used to treat pain. The pain may be, for example, acutepain (short duration) or chronic pain (reoccurring or persistent). Thepain may also be centralized or peripheral.

Examples of pain that can be acute or chronic and that can be treated inaccordance with the methods of the present invention includeinflammatory pain, musculoskeletal pain, bony pain, lumbosacral pain,neck or upper back pain, visceral pain, somatic pain, neuropathic pain,cancer pain, pain caused by injury or surgery, such as burn pain ordental pain, or headaches, such as migraines or tension headaches, orcombinations of these pains. One skilled in the art will recognize thatthese pains may overlap one another. For example, a pain caused byinflammation may also be visceral or musculoskeletal in nature.

In a preferred embodiment of the present invention the compounds usefulin the present invention, including compounds of formula (I), (II),(III), and pharmaceutically acceptable salts thereof, are administeredin mammals to treat chronic pain, such as neuropathic pain associatedfor example with damage to or pathological changes in the peripheral orcentral nervous systems; cancer pain; visceral pain associated with forexample the abdominal, pelvic, and/or perineal regions or pancreatitis;musculoskeletal pain associated with for example the lower or upperback, spine, fibromyalgia, temporomandibular joint, or myofascial painsyndrome; bony pain associated with for example bone or jointdegenerating disorders, such as osteoarthritis, rheumatoid arthritis, orspinal stenosis; headaches such migraine or tension headaches; or painassociated with infections, such as HIV, sickle cell anemia, autoimmunedisorders, multiple sclerosis, or inflammation, such as osteoarthritisor rheumatoid arthritis.

In a more preferred embodiment, the compounds useful in this invention,including compounds of formula (I), (II), (III), and pharmaceuticallyacceptable salts thereof, are used to treat chronic pain that isneuropathic pain, visceral pain, musculoskeletal pain, bony pain, cancerpain or inflammatory pain or combinations thereof, in accordance withthe methods described herein. Inflammatory pain can be associated with avariety of medical conditions, such as osteoarthritis, rheumatoidarthritis, surgery, or injury. Neurophathic pain includes peripheralneuropathic pain, central neuropathic pain or combinations thereof.Neuropathic pain may be associated with for example diabetic neuropathy,post-herpetic neuralgia, trigeminal neuralgia, complex regional painsyndrome, lumbar or cervical radiculopathies, fibromyalgia,glossopharyngeal neuralgia, reflex sympathetic dystrophy, causalgia,thalamic syndrome, nerve root avulsion, monoclonal gammopathy ofundetermined significance (MGUS) neuropathy, sarcoid polyneuropathy,HIV-related neuropathy arising from a variety of causes, such as frommedication used to treat HIV, peripheral neuropathy, such as peripheralneuropathy with connective tissue disease, paraneoplastic sensoryneuropathy, familial amyloid polyneuropathy, acquired amyloidpolyneuropathy, inherited neuropathy, neuropathy with renal failure,hereditary sensory autonomic neuropathy, Fabry's disease, Celiac diseaseor nerve damage cause by injury resulting in peripheral and/or centralsensitization, such as phantom limb pain, reflex sympathetic dystrophyor postthoracotomy pain, cancer including neuropathies caused bychemotherapy agents or other agents used to treat the disease, chemicalinjury, toxins, such as arsenic neuropathy, nutritional deficiencies, orviral or bacterial infections, such as shingles or HIV-relatedneuropathy, or combinations thereof. The methods of use for compounds ofthis invention further include treatments in which the neuropathic painis a condition secondary to metastatic infiltration, adiposis dolorosa,burns, or central pain conditions related to thalamic conditions.

Neuropathic pains described above may also be, in some circumstances,classified as “painful small fiber neuropathies”, such as idiopathicsmall-fiber painful sensory neuropathy, or “painful large fiberneuropathies”, such as demylinating neuropathy or axonal neuropathy, orcombinations thereof. Such neuropathies are described in more detail,for example, in the J. Mendell, et al., N. Engl. J. Med. 2003,348:1243-1255, which is hereby incorporated by reference in itsentirety.

As mentioned previously, the methods of the present invention may beused to treat pain that is somatic and/or visceral in nature. Forexample, somatic pain that can be treated in accordance with the methodsof the present invention include pains associated with structural orsoft tissue injury experienced during surgery, dental procedures, burns,or traumatic body injuries. Examples of visceral pain that can betreated in accordance with the methods of the present invention includethose types of pain associated with or resulting from maladies of theinternal organs, such as ulcerative colitis, irritable bowel syndrome,irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors,gastritis, pancreatitis, infections of the organs, or biliary tractdisorders, or combinations thereof. One skilled in the art will alsorecognize that the pain treated according to the methods of the presentinvention may also be related to conditions of hyperalgesia, allodynia,or both. Additionally, the chronic pain may be with or withoutperipheral or central sensitization.

The compounds useful in this invention, including compounds of formula(I), (II), (III), and pharmaceutically acceptable salts thereof, mayalso be used to treat acute and/or chronic pains associated with femaleconditions, which may also be referred to as female-specific pain. Suchgroups of pain include those that are encountered solely orpredominately by females, including pain associated with menstruation,ovulation, pregnancy or childbirth, miscarriage, ectopic pregnancy,retrograde menstruation, rupture of a follicular or corpus luteum cyst,irritation of the pelvic viscera, uterine fibroids, adenomyosis,endometriosis, infection and inflammation, pelvic organ ischemia,obstruction, intra-abdominal adhesions, anatomic distortion of thepelvic viscera, ovarian abscess, loss of pelvic support, tumors, pelviccongestion or referred pain from non-gynecological causes.

As mentioned previously, the term “treat” or “treating”, as used herein,is also meant to include totally or partially inhibiting (i.e.,preventing) the development of pain. Thus, compounds of the presentinvention may be administered to a mammal prior to the mammalexperiencing pain to partially or totally inhibit the development ofpain.

In some embodiments, the compounds useful in the present invention,including compounds of formula (I), (II), (III), and pharmaceuticallyacceptable salts thereof, may be administered prior to or during asurgical procedure to partially or totally inhibit development of painassociated with the surgical procedure. In a preferred embodiment, thecompounds useful in the present invention are preferably administeredfrom about 0.25 hours to about 4 hours prior to the surgical procedure.For surgical procedures of greater duration, dosing is preferablyrepeated during the surgical procedure about every time intervalcorresponding to the in vivo half life (T_(1/2)) of the compound.

In another embodiment of the present invention, it has been found thatadministering compounds useful in the present invention, includingcompounds of formula (I), (II), (III), and pharmaceutically acceptablesalts thereof, prior to a surgical procedure may increase the potencyand/or effectiveness of other pain relieving agents, such as opioidanalgesics (e.g., morphine) that are administered after the surgicalprocedure, and/or may reduce the amount of pain relieving agent neededto treat the post operative surgical pain. Thus, the present inventionprovides methods of treating pain associated with a surgical procedurethat includes administering prior to or during the surgical procedure acompound useful in the present invention, and administering after orduring a surgical procedure a therapeutically effective amount of atleast one pain relieving agent, such as an opioid analgesic. Inpreferred embodiments, compounds of the present invention may beadministered to a mammal also after the surgical procedure, preferablyin combination with the one or more pain relieving agents. “Surgicalprocedure,” as used herein, includes all therapeutic, diagnostic, and/orcosmetic manipulations, disruptions, movements, radiations, ablations,chemical or physical alterations in any tissue, organ, or body systemincluding but not limited to blood, blood vessels, fat, skin, connectivetissue, muscle, internal organs, glands, bone, cartilage, nerve, marrow,fascia, meninges, sensory apparatus, brain or spinal cord. Surgicalprocedure includes, for example, procedures performed on mammals usingmore recent surgical techniques, such as laser, ultrasound, andradiation in addition to more traditional techniques.

In another embodiment, the compounds useful in the present invention,including compounds of formula (I), (II), (III), and pharmaceuticallyacceptable salts thereof, may be administered to totally or partiallyinhibit a neuropathic pain condition from developing. For example,compounds of the present invention may be administered to a mammal thatis at risk for developing a neuropathic pain condition, such as a mammalthat has contracted shingles or a mammal that is being treated forcancer.

The compounds of the present invention can be administered in any wayknown to those skilled in the art, including for example, by oral orparenteral administration, such as by intramuscular, intraperitoneal,epidural, intrathecal, intravenous, subcutaneous, intramucosal, such assublingual or intranasal, vaginal, rectal or transdermal administration.In a preferred embodiment of the present invention, the compounds of thepresent invention are administered orally, intramucosally orintravenously.

The compounds of the present invention, including compounds of formula(I), (II), (III), and pharmaceutically acceptable salts thereof, areadministered in a therapeutically effective amount to the mammal needingtreatment. As used herein “a therapeutically effective amount” is atleast the minimal amount of the compound or a pharmaceuticallyacceptable salt form thereof, that treats the condition in question in amammal. The therapeutically effective amount will depend on suchvariables as the particular composition used, the route ofadministration, the severity of the symptoms, and the particular patientbeing treated. To determine the therapeutically effective amount of thecompound to be administered, the physician may, for example, evaluatethe effects of a given compound of formula (I), (II), (III), andpharmaceutically acceptable salts thereof, in the patient byincrementally increasing the dosage until the desired symptomatic relieflevel is achieved. The continuing dose regimen may then be modified toachieve the desired result. For example, in the case of an oral dosage,preferably the compounds of the present invention are incrementallyincreased in a patient in an amount of from 3 mg/kg to 1000 mg/kg untilthe desired symptomatic relief level is achieved. The continuing doseregimen may then be modified to achieve the desired result, with therange for oral dosage being preferably from about 20 mg/day to about1200 mg/day. Similar techniques may be followed by determining theeffective dose range for other administration routes, such as byintravenous or intramuscular routes based on bioavailability data.

In another embodiment of the present invention, the compounds of thepresent invention, including compounds of formula (I), (II), (III), andpharmaceutically acceptable salts thereof, may be administered to amammal with one or more other pharmaceutical active agents, such asthose agents being used to treat any other medical condition present inthe mammal. Examples of such pharmaceutical active agents include painrelieving agents, anti-angiogenic agents, anti-neoplastic agents,anti-diabetic agents, anti-infective agents, or gastrointestinal agents,or combinations thereof.

The one or more other pharmaceutical active agents may be administeredin a therapeutically effective amount simultaneously (such asindividually at the same time, or together in a pharmaceuticalcomposition), and/or successively with one or more compounds of thepresent invention, including compounds of formula (I), (II), (III), andpharmaceutically acceptable salts thereof.

The method of administration of the other pharmaceutical active agentmay be the same or different from the route of administration used forthe compounds of the present invention. For example, the otherpharmaceutical active agents may be administered by oral or parentaladministration, such as for example, by intramuscular, intraperitoneal,epidural, intrathecal, intravenous, intramucosal, such as by intranasalor sublingual, subcutaneous or transdermal administration. The preferredadministration route will depend upon the particular pharmaceuticalactive agent chosen and its recommended administration route(s) known tothose skilled in the art.

A more complete listing of pharmaceutical active agent can be found inthe Physicians' Desk Reference, 55th Edition, 2001, published by MedicalEconomics Co., Inc., Montvale, N.J. Each of these agents may beadministered according to the therapeutically effective dosages andregimens known in the art, such as those described for the products inthe Physicians' Desk Reference, 55th Edition, 2001, published by MedicalEconomics Co., Inc., Montvale, N.J.

In a preferred embodiment of the present invention, the compounds of thepresent invention, including compounds of formula (I), (II), (III), andpharmaceutically acceptable salts thereof, may be administered to amammal with one or more other pain relieving agents to treat pain in amammal. By “pain relieving agents” it is meant any agent that directlyor indirectly treats pain symptoms. Examples of indirect pain relievingagents include for example anti-inflammatory agents, such asanti-rheumatoid agents.

The one or more other pain relieving agents may be administeredsimultaneously (such as individually at the same time, or together in apharmaceutical composition), and/or successively with the compounds ofthe present invention. Preferably, the compounds of the presentinvention and the one or more pain relieving agents are administered ina manner so that both are present in the mammal body for a certainperiod of time to treat pain.

The method of administration of the other pain relieving agent may bethe same or different from the route of administration used for thecompound of the present invention. For example, opioids are preferablyadministered by oral, intravenous, or intramuscular administrationroutes.

One skilled in the art will recognize that the dosage of the other painrelieving agent administered to the mammal will depend on the particularpain relieving agent in question and the desired administration route.Accordingly, the other pain relieving agent may be dosed andadministered according to those practices known to those skilled in theart, such as those disclosed in references, such as the Physicians' DeskReference, 55th Edition, 2001, published by Medical Economics Co., Inc.,Montvale, N.J.

Examples of pain relieving agents that may be administered with thecompound of the present invention, including compounds of formula (I),(II), (III), and pharmaceutically acceptable salts thereof, includeanalgesics, such as non-narcotic analgesics or narcotic analgesics;anti-inflammatory agents, such as non-steroidal anti-inflammatory agents(NSAID), steroids or anti-rheumatic agents; migraine preparations, suchas beta adrenergic blocking agents, ergot derivatives, or isometheptene;tricyclic antidepressants, such as amitryptyline, desipramine, orimipramine; anti-epileptics, such as gabapentin, carbamazepine,topiramate, sodium valproate or phenytoin; α₂ agonists; or selectiveserotonin reuptake inhibitors/selective norepinepherine uptakeinhibitors, or combinations thereof. One skilled in the art willrecognize that some agents described hereinafter act to relieve multipleconditions, such as pain and inflammation, while other agents may justrelieve one symptom, such as pain. A specific example of an agent havingmultiple properties is aspirin, where aspirin is anti-inflammatory whengiven in high doses, but at lower doses is just an analgesic. The painrelieving agent may include any combination of the aforementionedagents, for example, the pain relieving agent may be a non-narcoticanalgesic in combination with a narcotic analgesic.

Non-narcotic analgesics useful in the present invention include, forexample, salicylates, such as aspirin, ibuprofen (MOTRIN®, ADVIL®),ketoprofen (ORUDIS®), naproxen (NAPROSYN®), acetaminophen, indomethacinor combinations thereof. Examples of narcotic analgesic agents that maybe used in combination with the cyclobutene derivatives include opioidanalgesics, such as fentenyl, sufentanil, morphine, hydromorphone,codeine, oxycodone, buprenorphine or pharmaceutically acceptable saltsthereof or combinations thereof. Examples of anti-inflammatory agentsthat may be used in combination with the cyclobutene derivatives includebut are not limited to aspirin; ibuprofen; ketoprofen; naproxen;etodolac (LODINE®); COX-2 inhibitors, such as celecoxib (CELEBREX®),rofecoxib (VIOXX®), valdecoxib (BEXTRA®), parecoxib, etoricoxib (MK663),deracoxib,2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine,4-(2-oxo-3-phenyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide,darbufelone, flosulide,4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide),meloxicam, nimesulide,1-methylsulfonyl-4-(1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl)benzene,4-(1,5-Dihydro-6-fluoro-7-methoxy-3-(trifluoromethyl)-(2)-benzothiopyrano(4,3-c)pyrazol-1-yl)benzenesulfonamide,4,4-dimethyl-2-phenyl-3-(4-methylsulfonyl)phenyl)cyclo-butenone,4-Amino-N-(4-(2-fluoro-5-trifluoromethyl)-thiazol-2-yl)-benzenesulfonamide,1-(7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-benzo-furanyl)-4-cyclopropylbutan-1-one, or their physiologically acceptable salts, esters orsolvates; sulindac (CLINORIL®); diclofenac (VOLTAREN®); piroxicam(FELDENE®); diflunisal (DOLOBID®), nabumetone (RELAFEN®), oxaprozin(DAYPRO®), indomethacin (INDOCIN®); or steroids, such as PEDIAPED®prednisolone sodium phosphate oral solution, SOLU-MEDROL®methylprednisolone sodium succinate for injection, PRELONE® brandprednisolone syrup.

Further examples of anti-inflammatory agents preferably used fortreating rheumatoid arthritis include naproxen, which is commerciallyavailable in the form of EC-NAPROSYN® delayed release tablets,NAPROSYN®, ANAPROX® and ANAPROX® DS tablets and NAPROSYN® suspensionfrom Roche Labs, CELEBREX® brand of celecoxib tablets, VIOXX® brand ofrofecoxib, CELESTONE® brand of betamethasone, CUPRAMINE® brandpenicillamine capsules, DEPEN® brand titratable penicillamine tablets,DEPO-MEDROL brand of methylprednisolone acetate injectable suspension,ARAVA™ leflunomide tablets, AZULFIDIINE EN-tabs® brand of sulfasalazinedelayed release tablets, FELDENE® brand piroxicam capsules, CATAFLAM®diclofenac potassium tablets, VOLTAREN® diclofenac sodium delayedrelease tablets, VOLTAREN®-XR diclofenac sodium extended releasetablets, or ENBREL® etanerecept products.

Examples of other agents used to treat inflammations, especiallyrheumatoid arthritis include immunosuppressants, such as GENGRAF™ brandcyclosporine capsules, NEORAL® brand cyclosporine capsules or oralsolution, or IMURAN® brand azathioprine tablets or IV injection;INDOCIN® brand indomethacin capsules, oral suspension or suppositories;PLAQUENIL® brand hydroxychloroquine sulfate; or REMICADE® infliximabrecombinant for IV injection; or gold compounds, such as auranofin orMYOCHRISYINE® gold sodium thiomalate injection.

In a preferred embodiment of the present invention, at least onecompound of the present invention is administered with at least oneopioid analgesic in accordance with the methods previously describedherein to treat pain. It has been found that the compounds of thepresent invention, when administered with at least one opioid analgesic,such as morphine, have such beneficial effects as synergisticallydecreasing pain perception, increasing the duration of pain relief,and/or decreasing adverse side effects.

The compounds of the present invention, including compounds of formula(I), (II), (III), and pharmaceutically acceptable salts thereof, may beadministered neat (i.e., as is) or in a pharmaceutical compositioncontaining at least one pharmaceutically acceptable carrier. Thus, thepresent invention also provides pharmaceutical compositions containing apharmaceutically effective amount of at least one compound of formula(I), (II), (III), and pharmaceutically acceptable salts thereof, and atleast one pharmaceutically acceptable carrier. Preferred compounds to bepresent in the pharmaceutical compositions of the present inventioninclude those compounds of formula (I), (II), (III), andpharmaceutically acceptable salts thereof previously described as beingpreferred. Pharmaceutically acceptable carriers are those that arecompatible with the other ingredients in the formulation andbiologically acceptable. The pharmaceutical compositions may beadministered to a mammal to treat a variety of conditions that wouldbenefit from inhibiting the NMDA receptor as previously describedherein.

Pharmaceutical compositions useful in the present invention may be inany form known to those skilled in the art, such as in liquid or solidform. The proportion of ingredients will depend on such factors as thesolubility and chemical nature of the compound of formula (I), (II),(III), and pharmaceutically acceptable salts thereof, and the chosenroute of administration. Such compositions are prepared in accordancewith acceptable pharmaceutical procedures, such as described inRemington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R.Gennaro, Mack Publishing Company, Easton, Pa. (1985).

Pharmaceutical compositions, in addition to containing a therapeuticallyeffective amount of one or more compounds of the present invention and apharmaceutically acceptable carrier may include one or more otheringredients known to those skilled in the art for formulatingpharmaceutical compositions. Such ingredients include for example,flavoring agents, lubricants, solubilizers, suspending agents, fillers,glidants, compression aids, binders, tablet-disintegrating agents,encapsulating materials, emulsifiers, buffers, preservatives,sweeteners, thickening agents, coloring agents, viscosity regulators,stabilizers or osmo-regulators, or combinations thereof.

Solid pharmaceutical compositions preferably contain one or more solidcarriers, and optionally one or more other additives, such as flavoringagents, lubricants, solubilizers, suspending agents, fillers, glidants,compression aids, binders or tablet-disintegrating agents or anencapsulating material. Suitable solid carriers include, for example,calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin,starch, gelatin, cellulose, methyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting waxes or ion exchangeresins, or combinations thereof. In powder pharmaceutical compositions,the carrier is preferably a finely divided solid which is in admixturewith the finely divided active ingredient. In tablets, the activeingredient is mixed with a carrier having the necessary compressionproperties in suitable proportions, and optionally, other additives, andcompacted into the desired shape and size. Solid pharmaceuticalcompositions, such as powders and tablets, preferably contain up to 99%of the active ingredient.

Liquid pharmaceutical compositions preferably contain one or morecompounds of the present invention and one or more liquid carriers toform for example solutions, suspensions, emulsions, syrups, elixirs, orpressurized compositions. Pharmaceutically acceptable liquid carriersinclude for example water, organic solvent, pharmaceutically acceptableoils or fat, or combinations thereof. The liquid carrier can containother suitable pharmaceutical additives, such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators, or combinations thereof.

Examples of liquid carriers suitable for oral or parenteraladministration include water (preferably containing additives, such ascellulose derivatives, such as sodium carboxymethyl cellulose), alcoholsor their derivatives (including monohydric alcohols or polyhydricalcohols, such as glycols) or oils (e.g., fractionated coconut oil andarachis oil). For parenteral administration, the carrier can also be anoily ester, such as ethyl oleate and isopropyl myristate. The liquidcarrier for pressurized compositions can be halogenated hydrocarbons orother pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be administered parenterally, for example by,intramuscular, intraperitoneal, epidural, intrathecal, intravenous orsubcutaneous injection. Pharmaceutical compositions for oral ortransmucosal administration may be either in liquid or solid compositionform.

The compounds of this invention, including compounds of formula (I),(II), (III), and pharmaceutically acceptable salts thereof, may beadministered rectally or vaginally in the form of a conventionalsuppository. For administration by intranasal or intrabronchialinhalation or insufflation, the compounds of this invention may beformulated into an aqueous or partially aqueous solution, which can thenbe utilized in the form of an aerosol. The compounds of this inventionmay also be administered transdermally through the use of a transdermalpatch containing the active compound and a carrier that is inert to theactive compound, is non toxic to the skin, and allows delivery of theagent for systemic absorption into the blood stream via the skin. Thecarrier may take any number of forms, such as creams and ointments,pastes, gels, and occlusive devices. The creams and ointments may beviscous liquid or semisolid emulsions of either the oil-in-water orwater-in-oil type. Pastes comprised of absorptive powders dispersed inpetroleum or hydrophilic petroleum containing the active ingredient mayalso be suitable. A variety of occlusive devices may be used to releasethe active ingredient into the blood stream, such as a semipermeablemembrane covering a reservoir containing the active ingredient with orwithout a carrier, or a matrix containing the active ingredient. Otherocclusive devices are known in the literature.

In another embodiment of the present invention, the pharmaceuticalcomposition, in addition to containing a compound of the presentinvention, including compounds of formula (I), (II), (III), andpharmaceutically acceptable salts thereof, may also contain atherapeutically effective amount of one or more pain relieving agents aspreviously described herein, and/or a therapeutically effective amountone or more other pharmaceutical active agents as previously describedherein. Thus, the present invention also provides a pharmaceuticalcomposition containing a therapeutically effective amount of at leastone compound of the present invention and a therapeutically effectiveamount of at least one pharmaceutical active agent, such as a painrelieving agent as previously described. For example, the pharmaceuticalcomposition may contain one or more pain relieving agents that includesan opioid analgesic.

Preferably, the pharmaceutical composition is in unit dosage form, suchas tablets or capsules. In such form, the composition is sub-divided inunit dose containing appropriate quantities of the active ingredient,including compounds of formula (I), (II), (III), and pharmaceuticallyacceptable salts thereof. The unit dosage forms can be packagedcompositions, for example packeted powders, vials, ampoules, pre-filledsyringes or sachets containing liquids. The unit dosage form can be, forexample, a capsule or tablet itself, or it can be the appropriate numberof any such compositions in package form.

Thus, the present invention also provides a pharmaceutical compositionin unit dosage form that contains a therapeutically effective unitdosage of at least one compound of the present invention. As one skilledin the art will recognize, the preferred unit dosage will depend on forexample the method of administration and the condition being treated.For example, a unit dosage for oral administration for treating painpreferably ranges from about 20 mg to about 300 mg of the compound ofthe present invention.

The present invention also provides a therapeutic package for dispensingthe compound of the present invention, including compounds of formula(I), (II), (III), and pharmaceutically acceptable salts thereof, to amammal being treated. Preferably, the therapeutic package contains oneor more unit dosages of the compound of the present invention and acontainer containing the one or more unit dosages and labeling directingthe use of the package for treating the condition, such as pain, in amammal. In a preferred embodiment, the unit dose is in tablet or capsuleform. In a preferred embodiment, each unit dosage is in atherapeutically effective amount for treating pain.

EXAMPLES

The following describes syntheses of exemplary compounds of Formula Idepicted by Scheme 1a, which is adapted from general Scheme 1 above.

Synthesis of IntermediatesDichloro Vinylphosphonate (i)

Trimethylsilyl bromide (150 mmol, 23 g) was added dropwise over 20minutes to a solution of dimethyl vinylphosphonate (40 mmol, 6.12 g) inmethylene chloride (100 mL) under stirring and dry nitrogen at ambienttemperature. The reaction mixture was stirred for 3 hours at ambienttemperature, evaporated under vacuo to dryness and the residue strippedtwo times with toluene (2×30 mL). The resultant faintly orange coloredoil was subjected to vacuum (1 Torr) overnight to afford 10 g (˜100%) ofthe silyl ester. The silyl ester (39.6 mmol, 10 g) was dissolved inmethylene chloride (20 mL) and dropwise added to a suspension ofphosphorous pentachloride (80 mmol, 16.7 g) in methylene chloride (100mL) under stirring and exclusion of moisture. A mild exothermic reactionwas noticed and the mixture was stirred for about one hour. Theresulting clear solution was evaporated in vacuo and the residuedistilled under reduced pressure. The fraction distilling at 63-66° C.and 16 Torr gave 5.2 g (90%) of the title compound as colorless oil.

Diethyl 3,3′-[(vinylphosphoryl)bis(oxy)]dibenzoate (3)

A solution containing ethyl-3-hydroxybenzoate (8 mmol, 1.329 g) andtriethylamine (8.3 mmol, 829 mg) in methylene chloride (50 mL) was addeddropwise at 0° C. under stirring to a solution of dichlorovinylphosphonate (4 mmol, 0.58 g) in methylene chloride (20 mL). Thereaction mixture was stirred at ambient temperature for 24 hours, washedtwice with water (40 mL each). The separated organic layer was washedwith brine, dried over magnesium sulfate, filtered and evaporated todryness in vacuo to yield 1.61 g (86-99%) of the desired title compound.MS (APPI+): m/e 405 [M+H]⁺.

2.6-Diaza-bicyclo[5.2.0]non-1(7)-ene-8,9-dione (2)

A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (20 mmol, 3.4 g) inmethanol (80 mL) and a solution of 1,3-diaminopropane (30 mmol, 2.23 g)in methanol (80 mL) were added dropwise in a parallel fashion over 10minutes under dry nitrogen at ambient temperature to methanol (130 mL)under vigorous stirring. Stirring was continued overnight after whichthe precipitated product was filtered and washed with ice-cold methanol(10 mL). The obtained faintly yellowish powder was dried in vacuum (1Torr) to yield 2.9 g (88-95%) of the desired title compound; mp 335° C.MS (ES−): m/e 151.1 [M−H]⁻.

Example 1 Diethyl3,3′-[({2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphoryl)bis(oxy)]dibenzoate

A suspension of 2.6-diaza-bicyclo[5.2.0]non-1(7)-ene-8,9-dione (2) (4mmol, 608 mg) in N,N-dimethylformamide (60 mL) was treated under drynitrogen and under stirring with 60% sodium hydride in oil (4.1 mmol,164 mg). After 30 minutes at ambient temperature the yellow reactionmixture was cooled to 0° C. and a solution of diethyl3,3′-[(vinylphosphoryl)bis(oxy)]dibenzoate (3) (4 mmol, 1.618 g) inN,N-dimethylformamide (30 mL) was added at once under vigorous stirring.The reaction mixture was then stirred at ambient temperature overnight,concentrated in vacuo and the residue partitioned between 5% aqueousammonium chloride solution and ethyl acetate (2×60 mL). The organiclayers were washed with brine, dried over magnesium sulfate, filteredand evaporated to dryness. The residue (>1.5 g) was flashchromatographed on silica gel (60 g). Elution with 2% methanol inchloroform afforded 600 mg (27%) of the desired title compound as awhite powder; mp 116-7° C. MS (ES+): m/e 557.2 [M+H]⁺.

Example 2 Diethyl2,2′-[({2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphoryl)bis(oxy)]dibenzoate

This compound is prepared in accordance with the synthesis of Example 1but starting from diethyl 2,2′-[(vinylphosphoryl)bis(oxy)]dibenzoate.

Example 3 Diethyl4,4′-[({2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphoryl)bis(oxy)]dibenzoate

This compound is prepared in accordance with the synthesis of example 1but starting from diethyl 4,4′-[(vinylphosphoryl)bis(oxy)]dibenzoate.

Example 4Bis(4-acetylphenyl){2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphonate

This compound is prepared in accordance with the synthesis of example 1but starting from vinyl-phosphonic acid bis-(4-acetyl-phenyl)ester.

Example 5Bis(3-acetylphenyl){2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphonate

This compound is prepared in accordance with the synthesis of Example 1but starting from vinyl-phosphonic acid bis-(3-acetyl-phenyl)ester.

Example 6Bis(2-acetylphenyl){2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphonate

This compound is prepared in accordance with the synthesis of Example 1but starting from vinyl-phosphonic acid bis-(2-acetyl-phenyl)ester.

Brief Description of Biological Test Procedure(s) and Summary of Results

Example 1 was synthesized and subjected to testing as described below.

Subjects

Individually housed Spraque-Dawley rats had free access to rat chow andwater. A 12-h light/12-h dark cycle was in effect (lights on from 6:00am to 6:00 pm). Animal maintenance and research were conducted inaccordance with the guidelines provided by the National Institutes ofHealth Committee on Laboratory Animal Resources. These subjects wereused in the tests below.

Procedure—Prostaglandin E₂-Induced Thermal Hypersensitivity:

The terminal 10 cm of the tail (rat) was placed into a thermos bottlecontaining water warmed to 38, 42, 46, 50 or 54° C. The latency inseconds for the animal to remove the tail from the water was used as ameasure of nociception. If the animal did not remove the tail within 20sec, the experimenter removed the tail and a maximum latency of 20 secwas recorded.

Following the assessment of baseline thermal sensitivity, thermalhypersensitivity was produced by a 50 μL injection of 0.1 mg ofprostaglandin E₂ (PGE₂) into the terminal 1 cm of the tail.Temperature-effect curves were generated before (baseline) and 30minutes after the PGE₂ injection. Previous studies in other species(e.g., monkeys; Brandt, et al., J. Pharmacol. Exper. Ther. 296:939,2001) and results from the current study demonstrate that PGE₂ producesa dose- and time-dependent thermal hypersensitivity that peaks 15 minafter injection and dissipates after 2 hours.

The ability of the compounds to reverse PGE₂-induced thermalhypersensitivity was assessed using a single dose time-course procedure.Under this procedure, a single dose of the compound to be tested wasadministered orally (PO) 10, 30, 100 or 300 min before the injection ofPGE₂. Tactile sensitivity was assessed 30 min after PGE₂ injection.Data Analysis—The temperature that produced a half-maximal increase inthe tail-withdrawal latency (i.e., T₁₀) was calculated from eachtemperature-effect curve. The T₁₀ was determined by interpolation from aline drawn between the point above and the point below 10 sec on thetemperature-effect curve. For these studies, thermal hypersensitivitywas defined as a leftward shift in the temperature-effect curve and adecrease in the T₁₀ value. Reversal of thermal hypersensitivity wasdefined as a return to baseline of the temperature-effect curve and theT₁₀ value and was calculated according to the following equation:${\%{MPE}} = {\frac{\left( T_{10}^{{drug} + {{PGE}\quad 2}} \right) - \left( T_{10}^{{PGE}\quad 2} \right)}{\left( T_{10}^{baseline} \right) - \left( T_{10}^{{PGE}\quad 2} \right)} \times 100}$in which T₁₀ ^(drug+PGE2) is the T₁₀ after a drug in combination withPGE₂, T₁₀ ^(PGE2) is the T₁₀ after PGE₂ alone, and T₁₀ ^(baseline) isthe T₁₀ under control conditions. A % MPE value of 100 indicates acomplete return to the baseline thermal sensitivity observed without thePGE₂ injection. A value of greater than 100% indicates that the compoundtested reduced thermal sensitivity more than the baseline thermalsensitivity without the PGE₂ injection.

Results: Example 1 of the present invention was effective in reversingPGE₂-induced thermal hypersensitivity by 40% at a dose of 10 mg/kg p.o.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges specific embodiments thereinare intended to be included.

The disclosures of each patent, patent application and publication citedor described in this document are hereby incorporated herein byreference, in its entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1-54. (canceled)
 55. A method for treating at least one condition in amammal selected from the group consisting of cerebral vascular disorderselected from the group consisting of cerebral ischemia, cerebralinfarction, cerebral vasospasm; cerebral trauma, and combinationsthereof; muscular spasm; a convulsive disorder selected from the groupconsisting of epilepsy, status epilepticus, and combinations thereof;hypoglycemia; cardiac arrest; asphyxia anoxia; spinal chord injury; andcombinations thereof, comprising the step of: administering to saidmammal a therapeutically effective amount of at least one compound offormula (I) or a pharmaceutically acceptable salt thereof:

wherein: A is alkylenyl of 1 to 4 carbon atoms, or alkenylenyl of 2 to 4carbon atoms; R₁ and R₂ are, independently, hydrogen, or C₅ to C₇ aryloptionally substituted with 1 to 2 substituents, independently, selectedfrom the group consisting of —C(O)R₃, halogen, cyano, nitro, hydroxylgroup, C₁-C₆ alkyl group, and C₁-C₆ alkoxy group, with the proviso thatat least one of R₁ and R₂ is not hydrogen; R₃ is, independently,hydrogen, —OR₄, alkyl, aryl, or heteroaryl, R₄ is hydrogen, alkyl, aryl,or heteroaryl, R₅ and R₆ are, independently, hydrogen, alkyl, OH,alkoxy, or C₅ to C₇ aryl; wherein any R₃ to R₆ group having an aryl orheteroaryl moiety can optionally be substituted on the aryl orheteroaryl moiety with 1 to about 5 substituents, independently,selected from the group consisting of halogen, cyano, nitro, hydroxyl,C₁-C₆ alkyl, and C₁-C₆ alkoxy.
 56. A method for treating at least onecondition in a mammal selected from the group consisting of glaucoma,diabetic and organ complications, and combinations thereof, comprisingthe step of: administering to said mammal a therapeutically effectiveamount of at least one compound of formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein: A is alkylenyl of 1 to 4 carbon atoms, or alkenylenyl of 2 to 4carbon atoms; R₁ and R₂ are, independently, hydrogen, or C₅ to C₇ aryloptionally substituted with 1 to 2 substituents, independently, selectedfrom the group consisting of —C(O)R₃, halogen, cyano, nitro, hydroxylgroup, C₁-C₆ alkyl group, and C₁-C₆ alkoxy group, with the proviso thatat least one of R₁ and R₂ is not hydrogen; R₃ is, independently,hydrogen, —OR₄, alkyl, aryl, or heteroaryl, R₄ is hydrogen, alkyl, aryl,or heteroaryl, R₅ and R₆ are, independently, hydrogen, alkyl, OH,alkoxy, or C₅ to C₇ aryl; wherein any R₃ to R₆ group having an aryl orheteroaryl moiety can optionally be substituted on the aryl orheteroaryl moiety with 1 to about 5 substituents, independently,selected from the group consisting of halogen, cyano, nitro, hydroxyl,C₁-C₆ alkyl, and C₁-C₆ alkoxy.
 57. A method for treating at least onecondition in a mammal selected from the group consisting of anxietydisorder, mood disorder, schizophrenia, schizophreniform disorder,schizoaffective disorder, and combinations thereof, comprising the stepof: administering to said mammal a therapeutically effective amount ofat least one compound of formula (I) or a pharmaceutically acceptablesalt thereof:

wherein: A is alkylenyl of 1 to 4 carbon atoms, or alkenylenyl of 2 to 4carbon atoms; R₁ and R₂ are, independently, hydrogen, or C₅ to C₇ aryloptionally substituted with 1 to 2 substituents, independently, selectedfrom the group consisting of —C(O)R₃, halogen, cyano, nitro, hydroxylgroup, C₁-C₆ alkyl group, and C₁-C₆ alkoxy group, with the proviso thatat least one of R₁ and R₂ is not hydrogen; R₃ is, independently,hydrogen, —OR₄, alkyl, aryl, or heteroaryl, R₄ is hydrogen, alkyl, aryl,or heteroaryl, R₅ and R₆ are, independently, hydrogen, alkyl, OH,alkoxy, or C₅ to C₇ aryl; wherein any R₃ to R₆ group having an aryl orheteroaryl moiety can optionally be substituted on the aryl orheteroaryl moiety with 1 to about 5 substituents, independently,selected from the group consisting of halogen, cyano, nitro, hydroxyl,C₁-C₆ alkyl, and C₁-C₆ alkoxy.
 58. The method of claim 57, wherein: saidanxiety disorder is panic attack, agoraphobia, panic disorder, specificphobia, social phobia, obsessive compulsive disorder, posttraumaticstress disorder, acute stress disorder, generalized anxiety disorder,separation anxiety disorder, substance-induced anxiety disorder, or acombination thereof; said mood disorder is bipolar disorder; saiddepressive disorder is major depressive disorder, dysthymic disorder,substance-induced mood disorder, or a combination thereof, and said moodepisode is major depressive episode, manic episode, mixed episode,hypomanic episode, or a combination thereof.
 59. A method for treatingat least one neurodegenerative disorder in a mammal selected from thegroup consisting of Parkinson's disease, Huntingdon's disease,Alzheimer's disease, amyotrophic lateral sclerosis, chronic dementia,cognitive impairment, and combinations thereof, comprising the step of:administering to said mammal a therapeutically effective amount of atleast one compound of formula (I) or a pharmaceutically acceptable saltthereof:

wherein: A is alkylenyl of 1 to 4 carbon atoms, or alkenylenyl of 2 to 4carbon atoms; R₁ and R₂ are, independently, hydrogen, or C₅ to C₇ aryloptionally substituted with 1 to 2 substituents, independently, selectedfrom the group consisting of —C(O)R₃, halogen, cyano, nitro, hydroxylgroup, C₁-C₆ alkyl group, and C₁-C₆ alkoxy group, with the proviso thatat least one of R₁ and R₂ is not hydrogen; R₃ is, independently,hydrogen, —OR₄, alkyl, aryl, or heteroaryl, R₄ is hydrogen, alkyl, aryl,or heteroaryl, R₅ and R₆ are, independently, hydrogen, alkyl, OH,alkoxy, or C₅ to C₇ aryl; wherein any R₃ to R₆ group having an aryl orheteroaryl moiety can optionally be substituted on the aryl orheteroaryl moiety with 1 to about 5 substituents, independently,selected from the group consisting of halogen, cyano, nitro, hydroxyl,C₁-C₆ alkyl, and C₁-C₆ alkoxy.
 60. A method for treating at least onecondition in a mammal selected from the group consisting of inflammatorydiseases; fibromyalgia; complications from herpes zoster; prevention oftolerance to opiate analgesia; withdrawal symptoms from addictive drugs,and combinations thereof, comprising the step of: administering to saidmammal a therapeutically effective amount of at least one compound offormula (I) or a pharmaceutically acceptable salt thereof:

wherein: A is alkylenyl of 1 to 4 carbon atoms, or alkenylenyl of 2 to 4carbon atoms; R₁ and R₂ are, independently, hydrogen, or C₅ to C₇ aryloptionally substituted with 1 to 2 substituents, independently, selectedfrom the group consisting of —C(O)R₃, halogen, cyano, nitro, hydroxylgroup, C₁-C₆ alkyl group, and C₁-C₆ alkoxy group, with the proviso thatat least one of R₁ and R₂ is not hydrogen; R₃ is, independently,hydrogen, —OR₄, alkyl, aryl, or heteroaryl, R₄ is hydrogen, alkyl, aryl,or heteroaryl, R₅ and R₆ are, independently, hydrogen, alkyl, OH,alkoxy, or C₅ to C₇ aryl; wherein any R₃ to R₆ group having an aryl orheteroaryl moiety can optionally be substituted on the aryl orheteroaryl moiety with 1 to about 5 substituents, independently,selected from the group consisting of halogen, cyano, nitro, hydroxyl,C₁-C₆ alkyl, and C₁-C₆ alkoxy.
 61. A method for treating pain in amammal, comprising the step of: administering to said mammal atherapeutically effective amount of at least one compound of formula (I)or a pharmaceutically acceptable salt thereof:

wherein: A is alkylenyl of 1 to 4 carbon atoms, or alkenylenyl of 2 to 4carbon atoms; R₁ and R₂ are, independently, hydrogen, or C₅ to C₇ aryloptionally substituted with 1 to 2 substituents, independently, selectedfrom the group consisting of —C(O)R₃, halogen, cyano, nitro, hydroxylgroup, C₁-C₆ alkyl group, and C₁-C₆ alkoxy group, with the proviso thatat least one of R₁ and R₂ is not hydrogen; R₃ is, independently,hydrogen, —OR₄, alkyl, aryl, or heteroaryl, R₄ is hydrogen, alkyl, aryl,or heteroaryl, R₅ and R₆ are, independently, hydrogen, alkyl, OH,alkoxy, or C₅ to C₇ aryl; wherein any R₃ to R₆ group having an aryl orheteroaryl moiety can optionally be substituted on the aryl orheteroaryl moiety with 1 to about 5 substituents, independently,selected from the group consisting of halogen, cyano, nitro, hydroxyl,C₁-C₆ alkyl, and C₁-C₆ alkoxy.
 62. A method according to claim 61,further comprising the step of: administering to said mammal atherapeutically effective amount of at least one pain relieving agent.63. A method according to claim 61, wherein said pain is neuropathicpain; cancer pain; visceral pain associated with pancreatitis, abdominalregion, pelvic region, or perineal region; musculoskeletal painassociated with lower or upper back, spine, fibromyalgia,temporomandibular joint, or myofascial pain syndrome; bony painassociated with bone or joint degenerating disorders; headache; or painassociated with infections, sickle cell anemia, autoimmune disorders,multiple sclerosis, dental procedures, burns or inflammation; or acombination thereof.
 64. A method according to claim 63, wherein saidpain comprises neuropathic pain and is associated with at least one ofdiabetic neuropathy; peripheral neuropathy; post-herpetic neuralgia;trigeminal neuralgia; lumbar radiculopathy; cervical radiculopathy;fibromyalgia; glossopharyngeal neuralgia; reflex sympathetic dystrophy;casualgia; thalamic syndrome; nerve root avulsion; nerve damage cause byinjury selected from the group consisting of phantom limb pain, reflexsympathetic dystrophy, postthoracotomy pain and combinations thereof;cancer; chemical injury; toxins; nutritional deficiencies; viralinfection, bacterial infection, and combinations thereof.
 65. A methodaccording to claim 61, wherein said pain is associated with small fiberneuropathy, large fiber neuropathy, peripheral neuropathy, or centralneuropathy.
 66. A method according to claim 61, wherein said pain ispost herpetic neuralgia.
 67. A method according to claim 61, whereinsaid pain is post-surgical pain.